B-12 - The Hidden Story

LOL about manure, Freddd.
It is hard to shed biases and just look openly at data. I do think we should keep this in mind. For instance someone who has had cancer or has a high risk of a certain type of cancer might want to monitor more closely. Clearly severe CFIDS is such a risk in itself that it's worth trying the protocol with caution and in low doses to start hopefully under a doctor's care.

"But I think there have been a few studies that indicate to me that supplements may have a dark side"

not to take supplements can have a darker side when someone has a chronic immune defficiency .. and in such a case to advise like dont take this dont do that just wait till ur dr can cure u can be more irresponsible than suggesting alternative ways

waiting witout a treatment with an ongoing infection , and with many ongoing infections in case of cfs , is a harmfull process as far as i know about infections .. in such a case , which supplement or any alternative treatment is more harmfull than cfs itself is an unanswered question .. so who or what is making more harm to pwc is also unanswered ..

to be cautious when starting anything let it be supplements or bungee jumping is a very good and clever advice tough

LOL about manure, Freddd.
It is hard to shed biases and just look openly at data. I do think we should keep this in mind. For instance someone who has had cancer or has a high risk of a certain type of cancer might want to monitor more closely. Clearly severe CFIDS is such a risk in itself that it's worth trying the protocol with caution and in low doses to start hopefully under a doctor's care.

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Hi Jenbooks,

It is hard to shed biases and just look openly at data.

That's the rub. It's exactly that reason that destroyed my life, made me undiagnosable to 100+ docs. That's why so many millions are suffering from stealth b12 deficiency and told "It's All In Your Head" and loaded up with psychiatric and anti seizure drugs instead of a couple of vitamins, 60 years of biases built upon a Nobel prize for a lab mistake. That's the reason 60 years of nutritional research built upon a false understanding is so terribly wrong. That's the reason success in treating CFS/FMS is so scarce. Ignorance is bad enough. Knowing something to be true that is false is even worse. The entire basis of treating all sorts of b12 deficiencies is entirely wrong, small doses every month or 3. There are hundreds of studies now demonstrating that the previous thousands are not so correct. Unfortunately almost everything most doctors and many researchers know about recognizing and treating the many various forms of b12 deficiencies is just plain wrong yet they will defend their "knowledge" to our graves. As always, it's people like us that suffer and pay for it.

Victory in The Senate We usually publish our newsletter on Tuesday. We held it overnight in order to report on the outcome of the Senate HELP Committee’s “FDA Food Safety Modernization Act” (Food Safety) mark up hearing. This hearing would decide whether to amend the dangerous Codex provision. The decision would have a momentous impact on the future of dietary supplements.

During the past few weeks, we met with most HELP Committee Senate offices to discuss our concerns and request an amendment to the Codex language in the Food Safety bill. Why were we so concerned? Because the original legislative language appeared to commit the US to the concept of harmonization of our food and supplement safety laws with a global standard. This global standard in turn is very likely to reflect European standards which are extremely hostile to dietary supplements.

Thanks to the amendment, the bill no longer requires the development of a plan “to harmonize requirements under the Codex Alimentarius”. Now the bill calls for a plan “on whether and how to harmonize requirements under the Codex Alimentarius" (§306, p. 116).

As will be evident, we have not succeeded in eliminating the Codex provision entirely. This is because the Senate wants to keep open the option of adopting some Codex rules while protecting dietary supplements from the harsh European regime. The language of the amendment means that we will have to remain very vigilant and probably refight the same battle over again in the future. But at least the US has avoided committing itself to the concept of Codex harmonization. And this is a very important legislative victory.

US law on dietary supplements is currently governed by The Dietary Supplement Health and Education Act (DSHEA). Senators Harkin and Hatch, strong supporters of natural health and the use of supplements, have assured us that asking the FDA to review Codex standards will not be allowed to threaten DSHEA. This is vital of course because of the FDA’s well known hostility to dietary supplements.

In his opening remarks in the mark up, Senator Harkin, chair of the HELP Committee, emphasized this message of protecting DSHEA. As the Senate moves forward with the legislation, Senators Harkin and Hatch have also promised to see what else can be done to make absolutely clear that none of its provisions will impact our access to high quality, potent dietary supplements.

There is more good news. The Senate Food Safety bill has eliminated many of the provisions in the House bill that most troubled us. However, we can’t forget that after the Senate passes it’s version of the Food Safety bill, the House and Senate will go to conference. There they will work behind closed doors to combine the Senate and House versions of the bill. This means that the worst provisions of the House bill could return.

Perhaps the most troubling aspect of the House bill is the increase in jail sentences (from three to ten years) and fines (to $100,000 for individuals and $7.5 million for corporations) for "adulterating" or "misbranding" food or supplements. If a food or supplement company cites scientific, peer-reviewed studies in support of a health benefit of a product, this would be deemed by the FDA to be misbranding and could trigger the penalties. Likewise, as defined in the current Good Manufacturing Practices, even minor paperwork violations could, per the FDA, represent adulteration and lead to draconian fines or jail sentences. These penalties are particularly worrying because of the FDA’s well established record of intimidation and legal harassment of innocent parties. It often seems that the FDA’s primary concern is to protect drugs from competition. Drug companies of course pay a significant portion of the FDA’s salaries.

The House bill also imposes new fees on food operations of all sizes, from the very smallest to the largest; imposes record keeping, hazard analysis, food safety plans, and more on farms as well as businesses, small and large; gives the FDA control of farming standards and practices, despite the Agency’s ignorance of these matters; permits the FDA to conduct random, warrantless searches; and ignores the recommendations of a government report on the failings of the FDA and the urgent need for reform at the Agency.

We will continue to work with members of Congress to ensure that the final version of the Food Safety bill does not compromise your access to healthy, natural and sustainable healthcare options, including high quality food and food supplements.

So I have a question. I'm trying really really hard to get my head around this whole methylation / POTS / B12s thing, but I have no idea why taking 1/2 tab of the Metafolin (instead of 1/4) has given me palpitations all morning? Why is dysautonomia caused by a lack of methylation, and thus active B vitamins? How long do I have to take the B12s to get reverse the dysautonomia (I know, how long's a piece of string...) Trying really hard to undestand here.... Any input gratefully received.

So I have a question. I'm trying really really hard to get my head around this whole methylation / POTS / B12s thing, but I have no idea why taking 1/2 tab of the Metafolin (instead of 1/4) has given me palpitations all morning? Why is dysautonomia caused by a lack of methylation, and thus active B vitamins? How long do I have to take the B12s to get reverse the dysautonomia (I know, how long's a piece of string...) Trying really hard to undestand here.... Any input gratefully received.

Nicola

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Hi, Nicola.

I'll answer your questions in terms of my hypothesis, so long as you understand that it is a hypothesis, and can't be viewed as proven, though I think there is quite a bit of evidence that supports it.

First, dysautonomia. This term means that the autonomic nervous system is not operating properly. I'm not convinced that this is always the correct diagnosis for people who experience either an increased heart rate or feel faint when they stand. In CFS, I believe that these problems are caused by a combination of low total blood volume, diastolic dysfunction of the heart, and blunting of the HPA axis.

I have suggested that all of these can be traced to glutathione depletion, which is part of the GD-MCB hypothesis. We have lots of test data showing glutathione depletion in CFS. There is also lots of evidence of diabetes insipidus (not the same as diabetes mellitus) in CFS. I've suggested that diabetes insipidus in CFS is caused by low glutathione in the hypothalamus, which leads to low production of antidiuretic hormone (this has been observed in a few PWCs). The diabetes indipidus causes excessive loss of water into the urine (observed). This lowers the total blood volume, even though the person is thirsty and drinks a lot of fluids (the blood volume has been measured in a few PWCs, and found to be low). The low total blood volume gives a low venous return to the heart. The low venous return, together with diastolic dysfunction of the heart, caused by low glutathione in the mitochondria of the heart muscle cells, causes low cardiac output, which is observed.

The HPA axis blunting produces poor control of the circulatory system by cortisol, which leads to low blood pressure. I've suggested that the HPA axis blunting in CFS is caused by low glutathione in the pituitary, which leads to low and faulty production of ACTH. This causes low and dysregulated cortisol output by the adrenals.

When the person stands up, the blood flow to the brain is insufficient because of all of the above. This can cause the person to feel faint. The deficient amount of blood present pools in the lower body, further decreasing the venous return and hence the cardiac output. This lowers the blood pressure further, causing orthostatic hypotension in some cases. Epinephrine (adrenaline) responds in an attempt to increase blood flow to the brain. That's what causes the increased heart rate in cases of POTS.

You asked about palpitations. I suspect that that is also a result of epinephrine secretion. It can also be caused by deficiencies in magnesium or potassium. Intracellular magnesium is low in CFS, and I have suggested that it is a result of low glutathione (There is evidence in the literature that this is true at least for red blood cells).

You asked why dysautonomia results from a methylation problem. If it is actually what I've described above, rather than real "dysautonomia," then I would suggest that it's because a partial block in the methylation cycle is linked to glutathione depletion. (We have lab test evidence that restoring the methylation cycle restores the level of glutathione.)

You asked why raising your dosage of Metafolin caused palpitations. I'm not sure, but generally, I have attributed the symptoms people have experienced during treatment to lift the partial block in the methylation cycle as being due to die-off of pathogens and/or mobilization of toxins, as the immune system and the detox system begin to operate more nearly normally again.

How long? Not sure about that, either. One person with a dysautonomic diagnosis experienced quite a bit of improvement in a few months time. The longest anyone has been on the treatment I've suggested for CFS is approaching three years, and there haven't been many on it that long. A small number have been able to return to full-time work, but most are still in treatment, though most have reported at least some improvement.

thanks for the explanation. What puzzles me about the orthostatic tachycardia is that I am on full adrenal hormone replacement (prednisolone and Florinef) so I am not sure that the low cortisol and low blood volume thing applies to me, or at least it shouldn't if I have got my dosing right. My blood pressure is normal and my intracellular magnesium is just below the top of the range, according to my last blood test. I know of people whose POTS was 'cured' by adrenal hormone support, so clearly something else is at play for me. The diastolic dysfunction is a distinct possibility - could this also cause the chest pain I wrote about it an earlier post? Is the dysfunction caused by low glutathione, or poor energy production, or a combination of both? Why would this get better with folate and B12? Does methylation play a role in energy production?

I subscribe to the view that the body reacts most strongly to the substances it needs the most - this has been my experience with a number of supplements - so I shall keep going with the methyl folate. I am surprised to have had a bigger reaction to the folate than the mB12 though, as I thought it was B12 that was depleted in mercury toxic people, not folate... Unless the folate is enabling the B12 to work more effectively... aah, so many questions and unknowns. And I really do want to understand all of this.

So I have a question. I'm trying really really hard to get my head around this whole methylation / POTS / B12s thing, but I have no idea why taking 1/2 tab of the Metafolin (instead of 1/4) has given me palpitations all morning? Why is dysautonomia caused by a lack of methylation, and thus active B vitamins? How long do I have to take the B12s to get reverse the dysautonomia (I know, how long's a piece of string...) Trying really hard to undestand here.... Any input gratefully received.

Nicola

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Hi Nicola,

I can't give you the type of answer Rich can on these things. I do have six years of experience with mb12 and cofactors. My doc was pretty clear about autonomic neuropathies for me. It took at least a couple of years for the POTS etc to clear up. I can't tell you exactly since there were no flashing lights saying "LAST TIME". It just slowly diminished in intensity and frequency until it just didn't show up again.

In my experience with a lot of people with active b12 and methylfolate startup, those who have a deficiency of methylfolate, as opposed to "less than optimum" but not clearly deficient, appear to have a problem utilizing mb12 and adb12. These folks tend to have mb12 and adb12 startup effects all roled into methylfolate startup effects. When I started methylfolate, the amount of mb12 I needed to inject before the first Just Noticable Difference in urine coloration went from 2.5mg SC to 4.375mg SC hours after the very first dose. When I took the glutathione precursors and had the outright folate deficiency symptoms the amount of b12 in my urine increased immediately to much more than before any methylfolate though I did not test what the minimum for a Just Noticable Difference was. That continued for the entire 6 week period and didn't return to normal for taking methylfolate until 6 months later when I took 4.8mg. Hours after the first increased dose of methylfolate, b12 completely disappeared from my urine for a few days and I had separate mb12 and adb12 startup efffects all over again after 6 years and 5 years 3 months respectively in the 2 active b12s despite not decreasing the dose during the glutathione precursors trial.

So perhaps, now that you are taking the methylfolate you will find the mb12 and adb12 much more effective. This is commonly reported. My S-I-L reported "methylfolate made the mb12 effective". He had little effect without methylfolate and big effect after.

You know what concerns me about the increased growth rate of cancer is the following.

Pain drug morphine may accelerate cancer growth

CHICAGO (Reuters) – Evidence is mounting that morphine, commonly used to manage pain, may accelerate cancer growth, but a newly-approved drug that blocks its side effects could also keep tumors from spreading, U.S. researchers said on Wednesday.

Prior lab studies by Singleton and colleague Jonathan Moss have shown that morphine can boost tumor cell growth and inhibit the immune response.

They also found that opiates promote the growth of new blood vessels, a process called angiogenesis, and can make blood vessels leaky, which could increase the chances that tumor cells in the blood can spread in the body.

Methylnaltrexone prevented lung tumor cells from spreading in lab dishes. Mice genetically altered to lack the opiate receptor called mu did not develop tumors when they were injected with cancer cells, but normal mice did.http://news.yahoo.com/s/nm/20091118...WNsZV9zdW1tYXJ5X2xpc3QEc2xrA3BhaW5kcnVnbW9ycA--
And in the one paragraph they said "opiates". Do they mean opiates or opioids? Does this apply to codeine, oxycodone and hydrocodone, hydromorphone and oxymorphone too? How about fentanyl?

As I am on morphine and have been for 9+ years now, this possible side effect of morphine does concern me. However, the inexactitude of reporting is disturbing. Why don't they say "opiates" instead of morphine if that is what they mean? Mixing the terms just confuses what they are saying. So now I don't know what they are really saying. Would changing to a differrent opioid cut down the risk or make no difference?

Or, are we seeing here a reporter that doesn't understand the difference between opioid and opiate and so on. Or did the different studies involved say different things and the reporter is trying to combine them? Or is the researcher purposely using inexact language because they are not clear on what they found?

Then they throw in the Mu receptor which implies most all opioids that affect the Mu receptor, not just opiates. So what indeed are they saying?

Hi Freddd, I did see that headline on google news. Most reporters don't understand or interpret the science very well so you need to go back to the original study. Does she reference where it was published??

Hi Freddd, I did see that headline on google news. Most reporters don't understand or interpret the science very well so you need to go back to the original study. Does she reference where it was published??

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Hi Jenbooks,

They give names of researchers. However, they are combining findings from a number of studies. The fuzzy factor is large in this article, probably since the reporter doesn't understand what is being read and combines carelessly.

It would be helpfull if the amount of increase in risk were also specified, at least in the situation they studied.

Well, I am sure you've done this before, but put the researchers' names into pubmed and get the abstracts, that's a start. Then see if the papers are publicly available in full text or if you need to belong to a university to get access. You can also just email the lead researcher, whose email should be on pubmed, and ask for a full PDF by email, indicating that you are on morphine and have concerns and want to bring the study to your doctor.

Freddd, I found a 2006 article by Patrick Singleton, the researcher quoted in the article that you mentioned. In the study, they were evaluating the effects of Morphine Sulphate (MS). It appears that morphine may promote angiogenesis and therefore possibly contribute to cancer growth. My interpretation is that morphine does not cause cancer, but if it is present, it can accelerate the disease process. Below is a link to the abstract. I've included the first few relevant paragraphs, but PM me if you want to read the whole article.

Angiogenesis is an essential phenotype in a number of physiologic and pathologic processes including growth and development (Risau, 1997), wound healing (Arnold and West, 1991) and reproduction (Welsh and Enders, 1991, Rogers et al., 1992 and Torry and Rongish, 1992). Inadequate angiogenesis contributes to ulcer formation (Folkman et al., 1991), while excessive angiogenesis contributes to the pathology of arthritis (Wilson, 2004), psoriasis (Creamer et al., 2002 and Leong et al., 2005) and neoplasia (Isayeva et al., 2004, Dhanabal et al., 2005 and Gaya and Rustin, 2005). In a series of now classical experiments, Folkman and colleagues demonstrated that solid tumors cannot grow larger than 2–3 mm in diameter unless they induce their own blood supply (Folkman et al., 1991 and Folkman, 1995).

Although morphine and other opioids are widely used to relieve cancer pain, surprisingly, few studies have considered the effect of opioids on angiogenesis or endothelial cell biology. The role of mu receptors, known to exist on endothelial cells (Cadet et al., 2004), remains unknown. The lack of a specific peripheral opioid antagonist has largely precluded clinical trials in this area because conventional tertiary opioid antagonists reverse analgesia with the reversal of peripheral effects. The development of methylnaltrexone (MNTX), a peripheral opioid antagonist now in phase III trials, offers an opportunity to examine the effect of opioids on endothelial cell biology (Yuan, 2004).

Using the endothelial cell migration assay, we found that MS caused a concentration-dependent increase in endothelial migration. Naloxone and MNTX alone had no effect on endothelial cell migration over a wide range of concentrations (Fig. 1A). At clinically relevant concentrations of morphine, the magnitude of the effect was approximately 70% of that achieved by VEGF. Endothelial cell migration was induced by morphine in concentrations as low as 10− 7 M (Fig. 1B). Morphine-based endothelial cell migration was attenuated by the mu opioid antagonists naloxone and MNTX (in doses as low as 10− 8 μM) in a concentration-dependent fashion, strongly suggesting that endothelial cell migration is mediated by morphine's action on the mu opiate receptor (MOR). That the effect is via the MOR rather than other opiate receptors was confirmed by our observations that the highly selective synthetic enkephalin DAMGO, a mu agonist, also induced migration in a concentration-dependent fashion. The effect of DAMGO was also blocked by MNTX (Fig. 1C). That the inactive morphine metabolite M3G exerts no migratory activity, while M6G, known to act at the mu receptor, exhibits a concentration-dependent effect on migration, confirms our hypothesis that morphine's effect on the endothelium is mediated by mu receptors (McQuay and Moore, 1997) (Fig. 1D).

I came across this methyl B12 lollipop that looks like it might be a good way to administer B12 to a child or disabled adult who aren't able to do sublingual B12. This company was founded by the father of an autistic spectrum child in an effort to make B12 in an easier to deliver form. About RevitaPop The lollipop contains 3.6 mg of Methylcobalamin.

Freddd, I found a 2006 article by Patrick Singleton, the researcher quoted in the article that you mentioned. In the study, they were evaluating the effects of Morphine Sulphate (MS). It appears that morphine may promote angiogenesis and therefore possibly contribute to cancer growth. My interpretation is that morphine does not cause cancer, but if it is present, it can accelerate the disease process. Below is a link to the abstract. I've included the first few relevant paragraphs, but PM me if you want to read the whole article.

Those paragraphs you included are interesting. As it so happens there is an intersection of some sort with mb12 here. Lack of mb12 can cause endothelial cell and endothelium changes and failure. It is via this endothelium malfuction that it is hypothecized that mb12 deficiency cause erectile dysfunction, edema, inflammation and other endothelial problems caused by a general failure of the tissue to be able to maintain, via adequate cell reproduction, itself in a healthy state. Lack of methylb12 is also connected with excess homocysteine which is damaging to endothelial cells.

Angiogenesis is an essential phenotype in a number of physiologic and pathologic processes including growth and development (Risau, 1997), wound healing (Arnold and West, 1991) and reproduction (Welsh and Enders, 1991, Rogers et al., 1992 and Torry and Rongish, 1992). Inadequate angiogenesis contributes to ulcer formation (Folkman et al., 1991), while excessive angiogenesis contributes to the pathology of arthritis (Wilson, 2004), psoriasis (Creamer et al., 2002 and Leong et al., 2005) and neoplasia

For the cells to actually reproduce and make new cells requires mb12 and methylfolate for DNA replication. A lack of these things certainly does slow down wound healing (ulcers and such resulting, also a common effect of mb12 deficiency) and other cell formation. It's possible that the increased rate of cell growth of the cancer specified is as compared to a chronically b12 deficient state and not some theoretical "healthy ideal". So the question might be whether b12 deficiency decreases the rate of cancer growth. In that case an induced b12 deficiency might be of value when trying to beat down cancer.

I came across this methyl B12 lollipop that looks like it might be a good way to administer B12 to a child or disabled adult who aren't able to do sublingual B12. This company was founded by the father of an autistic spectrum child in an effort to make B12 in an easier to deliver form. About RevitaPop The lollipop contains 3.6 mg of Methylcobalamin.

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Hi Kim,

Very interesting. Thankyou for telling me about it. Unfortunately it is loaded with sugar and is a real tooth rotter, especially if allowed to linger long enough to be absorbed well. I love the idea but the implementation leaves something to be desired.

My father, a dentist for a a couple of decades, had a sign on his wall.

It said "Candy is dandy but sex won't rot your teeth". Poor oral care is a large problem for many children and is a major problem with the autistic children because of much resistance to regular brushing and flossing. That was discussed at one conference I was at.

thanks for the explanation. What puzzles me about the orthostatic tachycardia is that I am on full adrenal hormone replacement (prednisolone and Florinef) so I am not sure that the low cortisol and low blood volume thing applies to me, or at least it shouldn't if I have got my dosing right. My blood pressure is normal and my intracellular magnesium is just below the top of the range, according to my last blood test. I know of people whose POTS was 'cured' by adrenal hormone support, so clearly something else is at play for me. The diastolic dysfunction is a distinct possibility - could this also cause the chest pain I wrote about it an earlier post? Is the dysfunction caused by low glutathione, or poor energy production, or a combination of both? Why would this get better with folate and B12? Does methylation play a role in energy production?

I subscribe to the view that the body reacts most strongly to the substances it needs the most - this has been my experience with a number of supplements - so I shall keep going with the methyl folate. I am surprised to have had a bigger reaction to the folate than the mB12 though, as I thought it was B12 that was depleted in mercury toxic people, not folate... Unless the folate is enabling the B12 to work more effectively... aah, so many questions and unknowns. And I really do want to understand all of this.

I really appreciate your input - it is deeply helpful. Thanks again.

Nicola

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Hi, Nicola.

Diastolic dysfunction is caused by too low a rate of production of ATP by the mitochondria of the heart muscle cells. The result is that the left ventricle cannot relax as fast as it should, so it cannot take in as much blood as it should. Therefore, the heart's output is less than it should be. In my hypothesis, this results from a rise in the levels of oxidizing free radicals in the mitochondria, which block the Krebs cycle and the respiratory chain. The free radicals rise because glutathione is depleted. There is good evidence for glutathione depletion in CFS. There is also good evidence for oxidative stress, and for low ATP output by mitochondria. Oxidizing free radicals are known to be able to block both aconitase in the Krebs cycle and some of the cytochrome enzymes in the respiratory chain.

In both CFS and autism, it has been found that glutathione depletion is linked to a partial block in the methylation cycle, and it has been found that if this partial block is lifted, glutathione comes up without direct supplementation of it or its precursors. Taking B12 and 5-methyl THF together have been found to lift this partial block, since both are needed by the enzyme methionine synthase, which is where the partial block is located.

When methyl B12 becomes deficient, either because B12 in general is deficient, or because there is a problem in converting B12 into methyl B12, the folate metabolites drain out of the cells into the blood plasma, by a mechanism called the "methyl trap." The methyl trap is based on the fact that almost the only way that 5-methyl tetrahydrofolate can react is in the methionine synthase reaction (though recent work indicates that it can also react with peroxynitrite). Also, 5-methyl tetrahydrofolate does not have a tail of glutamate residues, as do other folate metabolites, and therefore is able to exit the cells into the blood plasma. So when methionine synthase is blocked, much of the folate is converted into 5-methyl tetrahydrofolate and leaves the cells. So the cells then become deficient in both folates and methyl B12, and that's why it's necessary to supplement them together to get the methylation cycle running normally again.

I'm going to paste in an explanation of my hypothesis that I wrote some time ago. Hopefully this will help to put the pieces together. Again, please bear in mind that it is a working hypothesis, not a proven theory:

1. To get an isolated case of CFS (I'm not talking here about the epidemics or clusters), you have to have inherited some genetic variations from your parents. These are called polymorphisms or single-nucleotide polymorphisms. We know what some of the important ones are, but we don't know all of them yet. This is a topic that needs more research.

2. You also have to have some things happen in your life that place demands on your supply of glutathione. Glutathione is like a very small protein, and there is some in every cell of your body, and in your blood. It protects your body from quite a few things that can cause problems, including chemicals that are toxic, and oxidizing free radicals. It also helps the immune system to fight bugs (bacteria, viruses, fungi) so that you are protected from infections by them.

3. Oxidizing free radicals are molecules that have an odd number of electrons, and are very chemically reactive. They are normally formed as part of the metabolism in the body, but if they rise to high levels and are not eliminated by glutathione and the rest of the antioxidant system, they will react with things they shouldn't, and cause problems. This situation is called oxidative stress, and it is probably the best-proven biochemical aspect of chronic fatigue syndrome.

4. There are a variety of things in your life that can place demands on your glutathione. These include physical injuries or surgery to your body, exposure to toxic chemicals such as pesticides, solvents, or heavy metals like mercury, arsenic or lead, exposure to infectious agents or vaccinations, or emotional stress that causes secretion of a lot of cortisol and adrenaline, especially if it continues over a long time. Just about anything that "stresses" your body or your mind will place a demand on glutathione. All people experience a variety of stressors all the time, and a healthy person's body is able to keep up with the demands for glutathione by recycling used glutathione molecules and by making new ones as needed. However, if a person's body cannot keep up, either because of extra-high demands or inherited genetic polymorphisms that interfere with recycling or making glutathione, or both, the levels of glutathione in the cells can go too low. When glutathione is properly measured in most people with CFS (such as in the Vitamin Diagnostics methylation pathways panel), it is found to be below normal.

5. One of the jobs that glutathione normally does is to protect your supply of vitamin B12 from reacting with toxins. If left unprotected, vitamin B12 is very reactive chemically. If it reacts with toxins, it can't be used for its important jobs in your body. A routine blood test for vitamin B12 will not reveal this problem. In fact, many people with CFS appear to have elevated levels of B12 in their blood, while their bodies are not able to use it properly. The best test to reveal this is a urine organic acids test that includes methylmalonic acid. It will be high if the B12 is being sidetracked, and this is commonly seen in people with CFS.

6. When your glutathione level goes too low, your B12 becomes naked and vulnerable, and is hijacked by toxins. Also, the levels of toxins rise in the body when there isn't enough glutathione to take them out, so there are two unfortunate things that work together to sabotage your B12 when glutathione goes too low.

7. The most important job that B12 has in the body is to form methylcobalamin, which is one of the two active forms of B12. This form is needed by the enzyme methionine synthase, to do its job. An enzyme is a substance that catalyzes, or encourages, a certain biochemical reaction.

8. When there isn't enough methylcobalamin, methionine synthase has to slow down its reaction. Its reaction lies at the junction of the methylation cycle and the folate cycle, so when this reaction slows down, it affects both these cycles.

9. The methylation cycle is found in all the cells of the body (not counting the red blood cells, which are unusual in a lot of ways). The methylation cycle has some important jobs to do. First, it acts as a little factory to supply methyl (CH3) groups to a large number of reactions in the body. Some of these reactions make things like creatine, carnitine, coenzyme Q10, phosphatidylcholine, melatonin, and lots of other important substances for the body. It is not a coincidence that these substances are found to be low in CFS, so that people try taking them as supplements. Not enough of them is being made because of the partial block in the methylation cycle. The methylation cycle also supplies methyl groups to be attached to DNA molecules, and this helps to determine whether the blueprints in the DNA will be used to make certain proteins according to their patterns. The "reading" of DNA is referred to as "gene expression." Methyl groups prevent or "silence" gene expression. Overexpression of genes has been observed in CFS patients, and I suspect this is at least partly due to lack of sufficient methylation to silence gene expression.

10. Another thing that the methylation cycle does is to regulate the overall use of sulfur in the body. Sulfur comes in from the diet in the form of amino acids in protein (methionine and cysteine) and as taurine and some as sulfate. The methylation cycle regulates the production of the various substances that contain sulfur that are needed by the body. The levels of various sulfur metabolites are often found to be abnormal in people with CFS.

11. One of the most important sulfur-containing substances in the body is glutathione, so now you can see how this is starting to look like a dog chasing its tail! The thing that causes chronic fatigue syndrome to be chronic, and keeps people ill for years and years, is this interaction between glutathione, vitamin B12, and the methylation cycle. When glutathione goes too low, the effect on vitamin B12 slows down the methylation cycle too much. The sulfur metabolites are then dumped into the transsulfuration pathway (which is connected to the methylation cycle) too much, are oxidized to form cystine, pass through hydrogen sulfide, and are eventually converted to thiosulfate and sulfate and are excreted in the urine. This lowers the production of glutathione, which requires cysteine rather than cystine, and now there is a vicious circle mechanism that preserves this malfunction and keeps you sick.

12. That's the basic biochemical mechanism of CFS. I believe that everything else flows from this. As you know, there are many symptoms in CFS. I won't discuss all of them in detail here, but here's how I believe the fatigue occurs: The cells have little powerplants in them, called mitochondria. Their job is to use food as fuel to produce ATP (adenosine triphosphate). ATP acts as a source of energy to drive a very large number of reactions in the cells. For examples, it drives the contraction of the muscle fibers, and it provides the energy to send nerve impulses. It also supplies the energy to make stomach acid and digestive enzymes to digest our food, and many, many other things.

When glutathione goes too low in the muscle cells, the levels of oxidizing free radicals rise, and these react with parts of the "machinery" in the little powerplants, lowering their output of ATP. So the muscle cells then experience an energy crisis, and that's what causes the fatigue. Over time, because of the lack of enough glutathione, more problems accumulate in the mitochondria, including toxins, viral DNA, and mineral imbalances. These have been observed in the ATP Profiles and Translocator Protein test panels offered by Acumen Lab in the UK.

13. There are explanations that flow from this basic mechanism for other aspects of CFS. I haven't figured out explanations for all of the aspects of CFS, but I do think I understand a large number of them in some detail, and I've been able to explain enough of them that I believe this mechanism will account for the rest as well, if we can figure out the underlying biochemistry. My 2007 IACFS conference poster paper presented outlines of many of these explanations.

14. The involvement of infections by bacteria, viruses and fungi appears to have two aspects in CFS. First, as mentioned above, infectious agents can act as one of the stressors that initially bring down the level of glutathione and produce the onset of isolated cases of CFS in people who are genetically susceptible. I suspect that the clusters or epidemic occurrences of CFS (such as at Incline Village in the mid-80s) were caused by particularly virulent infectious agents, such as powerful viruses, and the genetic factor is less important in these cases.

15. Second, when a person's glutathione, methylation cycle, and folate cycle are not operating normally because of the vicious circle described above, the immune system does not function properly. In this case, viruses and bacteria that reside inside our cells and that are always in the body in their dormant, resting states are able to reactivate and produce infections, which the immune system is not able to totally put down. This accounts for the observation that most of the viral and intracellular bacterial infections seen in CFS patients are caused by pathogens that most of the population is carrying around in their dormant states.

16. Third, when the immune system's defenses are down, a person can catch new infections from others or from the environment, and the immune system is not able to defeat them, so they accumulate over time. Dr. Garth Nicolson has found that the longer a person has been ill, the more infections they have, on the average.

17. Other things that accumulate over time are various types of toxins, because the detox system depends to a large extent on the sulfur metabolism, and it will not be operating properly as long as the person has CFS. The body stores much of these toxins in fat, but as the levels get higher, they begin cause problems throughout the biochemistry of the cells. Many people with CFS have been tested for toxins (most commonly the heavy metal toxins, which are the most easily tested) and they are commonly found to be elevated.

18. The longer a person is chronically ill with CFS, the more toxins and infections accumulate in their body, and the more symptoms they experience. This explains why the disorder changes over time, and why some people become extremely debilitated after being ill for many years.

19. The main key to turning this process around is to help the methionine synthase enzyme to operate more normally, so that the partial block in the methylation cycle and the folate cycle are lifted, and glutathione is brought back up to normal. That is what the simplified treatment approach is designed to do, and so far, the evidence is that it does do these things in most people who have CFS. I recommend that people with CFS have the Vitamin Diagnostics methylation pathways panel run to find out if they do in fact have a partial methylation cycle block and glutathione depletion before deciding, with their doctors, whether to try this treatment. This also provides a baseline so that progress can be judged later on by repeating it every few months during the treatment. Symptoms may not be a good guide to judge progress during treatment, because detoxing and die-off can make the symptoms worse, while in fact they are exactly what is needed to move the person toward recovery.

20. The main question I'm working on now is what else needs to be done to bring people to recovery? I don't have complete answers to this question yet. Many people may recover from this treatment alone, but it is proving to be a slow process, and we will need more time to see how this will work out. It does appear that people who suffer from illness due to toxic molds do need to remove themselves from environments where these are present. The small amount of evidence I have so far suggests that people who have Lyme disease will need to have that treated in addition. I'm not sure about certain viral infections. They may also need to be treated. We still have a lot to learn, but I'm convinced that the mechanism I have described above is the core of the abnormal biochemistry in CFS, and correcting it needs to be cornerstone of the treatment.

I've been reading the B12/methylation information for some time now and not until I read your post to Nicola did I feel like I have some understanding of what the aim of the protocol is. Thank you so much for taking the time to write it all out so clearly.

When glutathione is properly measured in most people with CFS (such as in the Vitamin Diagnostics methylation pathways panel), it is found to be below normal.

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I posted this on the XMRV/autism thread as well, because there has been some confusion about how to get in touch with Vitamin Diagnostics. The contact information below was listed by several sources.

[a total OT aside: Keyport is a tiny industrial town on the Raritan Bay, just south of the New York Harbor. I haven't been there since I was a teenager - in a parked car down a secluded road with a boy - in the summer that I got Mono that started this whole illness. Funny how it all comes full circle]

That is a most interesting hypothesis on how this whole vicious cycle fits together and clearly shows the multiple places at which it is vulnerable to interuption..

It also makes sense then in terms of plenty of methylb12, adb12, methylfolate, l-carnitine fumarate breaking that cycle way open in multiple places by reestablishing the ATP production with the adb12 and l-carnitine fumarate, ample methylb12 to perform all it's functions including detoxification of many toxins and destruction and inactivation of some of the methylb12 thereby but having ample left to perform all required tasks including cofactors such as methylfolate and p-5-p in the homocystein-methionine conversion and DNA replication, functional neurology, healing the neurology and neuropathies including the autonomic neuropathies up to those of the subacute combined degeneration level in the worst of cases which present more of a problem.

From what you say there then using the active b12s and methylfolate gets around the many problems locking folks into the loop in the first place by directly counteracting it in every way. Since it is present in large quantities it doesn't need protection by glutathione and instead detoxifies the toxins and they are excreted removing the problem.

And indeed, attacking the problem on multiple fronts does cause a return to normal funtioning in many ways or reveals more clearly the comorbidities causing continuing problems. As many are finding out, severe abnormal fatigue, brainfog and and many other symptoms can be reduced or eliminated relatively quickly. Damage takes a while to heal however, some forms of damage much longer than other forms to heal. Fortunately most of it heals. Recovery from years of inactivity and reconditioning takes longer however and requires exercise. CNS damage takes longest to heal and appears least likely to heal completely. However, many things don't heal until the last critical cofactor is in place and I don't believe that we have found all of those yet.

The comorbidity issues, including continued fungal erxposure, viral and/or bacterial infections are a continued and complicating factor. Whether it is a post infection crash which keeps going by it's own momentum because of the lock-in factors you mention and from which one can break the cycle with the right forms of the vitamins or an actual ongoing infection, it presents additional challanges. I found high dose vitamin C as suggested by Linus Pauling (16 grams a day) instrumental in overcoming the ongoing infection I had as evidenced by years/decades of chronic swollen glands and frequent fevers. Also, methylb12 appears to significantly improve immune functioning. I used to have 6 streps a year, catch every miscellanious thing going around, pneumonia every few year and all the rest. Much to my surprise I haven't been ill in 6 years which is 5.5 years longer than at any other previous time in my life though it's sometimes hard to tell when one has more or less continuous infections, just when and where one stops and another begins. It often took me 2-6 months to shake a cold and resulting bronchitus and/or pneumonia. I went for years at a time never being clear of one thing or another. I used to live on antibiotics from before the age of 2. My current doc for the past 6 years has never presribed one for me. The only one of recent years was for an infected root canal that a sloppy dentist caused me to get.